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Abstract:

A matrix formulation for a soft chewable capsule is provided which
includes a gel-forming composition, a plasticizer, a polymer modifier,
and water. The polymer modifier may be a carboxylic acid or other organic
compound that alters the physical and/or chemical properties of the
capsule formulation. A chewable soft capsule is also provided, having
enhanced organo-leptic and processing properties. An active material may
be delivered to a user using this dosage form. A method of forming the
chewable soft capsule is also provided.

Claims:

1. A method of making a chewable soft capsule comprising: combining a
gel-forming composition comprising a polymer, oligomer, monomer, polymer
hydrolysate, or combinations thereof, with a polymer modifier; incubating
the combined gel-forming composition and polymer modifier for a
sufficient time to form a flowable matrix; and, encapsulating the matrix
to form a chewable soft capsule.

2. The method of claim 1, wherein said polymer modifier is an acid.

3. The method of claim 1, wherein said polymer modifier is selected from
the group consisting of a carboxylic acid, lactic acid, fumaric acid,
tartaric acid, citric acid, glycolic acid, salts of the foregoing, and
combinations of the foregoing.

4. The method of claim 1, wherein said polymer modifier is citric acid.

5. The method of claim 1, wherein the matrix comprises about 0.1 to about
10 percent by weight polymer modifier.

6. The method of claim 1, wherein the matrix comprises about 0.25 to
about 5 percent by weight polymer modifier.

7. The method of claim 1, wherein the combining step further comprises
adding water and a plasticizer to the gel-forming composition.

8. The method of claim 1, wherein the gel-forming composition is a
gelatin exhibiting a bloom in the range of about 20 to about 250.

9. The method of claim 1, wherein the gel-forming composition is a
gelatin exhibiting a bloom in the range of about 40 to about 80.

10. The method of claim 1, wherein the encapsulating step comprises
combining the matrix with a sheath, said sheath comprising a gel-forming
polymer and a plasticizer.

11. The method of claim 1, wherein the incubating step is for about 4 to
about 72 hours.

12. The method of claim 1, wherein the temperature of the combined
gel-forming composition and polymer modifier is maintained in a range of
about 40.degree. C. to about 75.degree. C. during the incubating step.

13. The method of claim 1, further comprising cooling the matrix prior to
the encapsulating step.

14. The method of claim 1, further comprising adjusting the water content
of the chewable soft capsule to a range of about 5 to about 20 percent by
weight.

15. A method of forming a chewable soft capsule for administering an oral
dosage of an active ingredient comprising the steps of: mixing a gelatin
composition, a plasticizer, a polymer modifier and water together to form
a matrix, wherein the gelatin composition exhibits a bloom in the range
of about 20 to about 250, wherein the plasticizer includes a polyol, and
wherein the polymer modifier includes a carboxylic acid; incubating the
matrix; cooling the matrix; encapsulating the matrix in a sheath, wherein
the sheath includes a plasticizer and a gelatin that exhibits a bloom in
the range of about 80 to about 250.

16. The method of claim 15, wherein the temperature of the matrix is
maintained in a range of about 40 to about 75 degrees Celsius during the
incubating step.

17. The method of claim 15, wherein the incubating step is carried out
over a time period of about 4 to about 72 hours.

18. The method of claim 15, wherein the matrix includes from about 0.1 to
about 10 percent by weight carboxylic acid.

Description:

RELATED APPLICATIONS

[0001] The present application is a divisional of U.S. patent application
Ser. No. 10/512,318, filed Oct. 22, 2004, which is a national stage
application under 35 U.S.C. §371 of International Application Serial
No. PCT/US03/12983, filed Apr. 24, 2003, which claims benefit of priority
under 35 U.S.C. §119 to U.S. Provisional Patent Application Ser. No.
60/375,479, filed on Apr. 25, 2002, the contents of each are hereby
incorporated by reference in their entirety.

TECHNICAL FIELD

[0002] The present invention relates generally to a chewable matrix
composition. The invention also relates to chewable soft capsules and to
a process for their preparation, and in particular to chewable soft
capsules having a controllable chewable consistency.

BACKGROUND

[0003] Chewable dosage forms are manufactured as solids, such as chewable
tablets, or elastic semi-solids such as chewing gums, molded gels, or
chewable soft capsules. While elastic semi-solid forms provide better
mouth feel and customer acceptance, chewable soft capsules have a further
benefit of being totally ingestible and can deliver accurate amounts of
active ingredients.

[0004] Soft capsules formed of a sheath encapsulating a fill or a matrix
are one type of dosage form generally used for administering perorally a
medicament, vitamin, nutritional supplement, or other material. Certain
types of these soft capsules are designed to be chewed by the user.
Chewable soft capsules, or chewable soft gels, are traditionally designed
so that the user chews upon the capsule to release the fill into the
mouth, instead of swallowing the capsule with the fill still encapsulated
within the sheath. Chewable capsules are particularly suitable for
administering analgesics, vitamins, minerals and cold remedies. After the
fill has been released, the user chews the fractured sheath until it is
partially or completely dispersed. Alternatively, the sheath may include
a chewing gum base material that is not made for swallowing.

[0005] Although chewable soft capsules provide an effective dosage system,
user acceptance has been limited by the capsules' organo-leptic
properties, which are sometimes criticized as being leathery or rubbery,
as well as the difficulty that some users experience in consuming the
fractured sheaths after the fills have been released. Current soft
capsules share the disadvantage of having a distinguishable difference
between the sheath and fill in terms of texture and mouth-feel. In
addition, they tend to harden over time. The objective of this invention
is to address these issues and limitations.

SUMMARY

[0006] The present invention is directed generally to a soft capsule
useful as a dosage delivery system. The soft capsule, when used as an
oral dosage form, exhibits a consistency, texture and other organo-leptic
properties found desirable in a chewable capsule. The capsule, which is
suitable for chewing, generally includes a gel-forming polymer, a
plasticizer, a polymer modifier, and, water. The capsule also includes an
active ingredient that is to be delivered to the user, and optionally
contains flavoring agent, sweetener, and/or a taste-masking agent.

[0007] In one embodiment, the soft capsule generally includes a matrix
encapsulated in a sheath. The matrix is formed of a gel-forming polymer,
a first plasticizer, water and a polymer modifier. The sheath is formed
of a second gel-forming polymer and a second plasticizer. The active
ingredient may be contained within the matrix. One or both of the first
and second gel-forming polymers may be a gelatin that exhibits a bloom in
a predetermined range.

[0008] In one particular embodiment, the matrix includes a gelatin
exhibiting a bloom in the range of about 0 to about 250. The sheath
includes a gelatin that exhibits a bloom in the range of about 80 to
about 250.

[0009] In another embodiment, the soft capsule has a matrix formed of a
gelatin that exhibits a bloom in the range of about 0 to about 80 and a
sheath that exhibits a bloom in the range of about 100 to about 150.

[0010] In yet another embodiment, the matrix includes a gelatin exhibiting
a bloom in the range from about 20 to about 250.

[0011] In yet another embodiment, the matrix includes a gelatin exhibiting
a bloom in the range from about 40 to about 80.

[0012] The polymer modifier used to form the matrix of the soft capsule of
the present invention generally includes a carboxylic acid. In one
embodiment, the polymer modifier used to form the matrix of the soft
capsule is selected from lactic acid, fumaric acid, tartaric acid, citric
acid, glycolic acid, and combinations thereof.

[0013] The plasticizer used to form the matrix and/or sheath of the soft
capsule may include a polyol. In another particular embodiment, the soft
capsule is formed using a plasticizer selected from glycerol, sorbitol,
maltitol, xylitol, and combinations thereof.

[0014] A method of making a soft capsule is also encompassed by the
present invention. The method generally includes the step of combining a
gel-forming polymer with a polymer modifier, incubating the combined
gel-forming polymer and polymer modifier to form a matrix; and,
encapsulating the matrix to form a chewable soft capsule.

[0015] In one embodiment, the method of forming a chewable soft capsule
for administering an oral dosage of an active ingredient includes the
steps of: mixing a gelatin, a plasticizer, a polymer modifier, and water
together to form a matrix, incubating the matrix, cooling the matrix, and
encapsulating the matrix in a sheath. In this embodiment, the gelatin
exhibits a bloom in the range of about 0 to about 250 and the plasticizer
includes a polyol. Also, the polymer modifier includes a carboxylic acid
and the sheath includes a plasticizer and a gelatin that exhibits a bloom
in the range of about 80 to about 250.

[0016] These and other embodiments and advantages are contemplated by the
present invention, which is set forth in detail below.

DETAILED DESCRIPTION

[0017] This invention provides chewable soft gel compositions that
minimize or reduce the traditional user's complaints regarding a
perceived major difference in texture between the matrix and the capsule
shell or sheath that is a result of the current technology. Therefore,
this invention describes chewable softgel compositions with homogeneous,
controllable mouth-feel for the whole capsule.

[0018] The soft gel is made from a hydrophilic matrix comprising a
gel-forming polymer and its oligomers or hydrolysates, in presence of a
polymer modifier that can control the texture, viscosity, and melting
point of the matrix. In addition, the sheath comprises a polymer
modifier, along with the gel-forming polymer composition, and
plasticizer. Such a combination has the benefit of providing a stable
composition where mass transfer between the shell and the matrix is
reduced due to the structural similarity between the matrix and the
shell.

[0019] A soft capsule exhibiting organo-leptic properties that are
appropriate for use as a chewable dosage form for delivering therapeutic,
diagnostic, and/or dietary agents is set forth herein. The organo-leptic
properties of the soft capsule, such as, for example, texture, and
chewiness, are enhanced by the polymer modifier included in the capsule
formulation. In addition, the polymer modifier enhances the physical
and/or chemical properties of the gel-forming polymers that are used to
form the capsule matrix and/or sheath, thereby facilitating the
processing of the soft capsule. The soft capsules generally include a
hydrophilic, watersoluble matrix that includes one or more active
ingredients and is encapsulated in hydrophilic, water-soluble sheath. The
matrix and the sheath are generally formed of similar materials, although
variations in their compositions are contemplated by the present
invention.

[0020] As used herein, the terms "gel-forming polymer" and "gel-forming
composition" refer to any natural or synthetic polymeric material or
partial hydrolysate of a polymer that can form a gel when appropriately
dissolved or dispersed in water or aqueous media. Examples of gel-forming
compositions include proteins such as different types of gelatins from
different sources. Specific examples are: acid and lime bone bovine
gelatins; pig bone gelatin; skin pig gelatin; skin bovine gelatin; and
fish gelatin. Other examples of gel-forming compositions are of
polysaccharide nature. Specific examples are: sodium and calcium
alginate; natural and modified starch and starch hydrolysates; pectins
and amylopectins; and cellulose derivatives, such as hydroxypropyl-methyl
cellulose, and carboxymethyl cellulose, and salts thereof. A gel-forming
composition can be a hydrophilic polymer, alone or in combination with
its building units, its oligomers, or hydrolysate. As used in the present
description, the term "active ingredient" is intended to include
therapeutic, diagnostic or nutritional agents, such as medicaments,
vitamins, minerals, fruit extracts, herbals and other encapsulatable
materials that are intended for local effect in the mouth or the
gastro-intestinal tract, or for systemic effect, or combinations thereof
understood by those skilled in the art to support the desired effect.
Examples of active ingredients useful in this application are:
anti-asthmatic drugs such as salbutamol, theophylline; anti-epileptic
drugs such as phenytoin; analgesics such as paracetamol, naproxen,
ibuprofen, aspirin, meloxicam, and celecoxib; nonsteroidal
anti-inflammatory drugs (NSAIDs); beta-lactam antibiotics such as
amoxycillin; macrolide antibiotics such as azythromycin, and
clarythromycin; mineral supplements, such as iron, potassium, calcium,
magnesium supplements and salts thereof; and vitamins, such as vitamins
C, B complex, A, E, K, and D; and other food supplements.

[0021] As used herein, "polymer modifier" refers to a pharmaceutically
acceptable compound that has the ability, under the appropriate process
conditions, to alter one or more physical and/or chemical properties of
one or more of the gel-forming polymers disclosed herein or generally
known for use in soft capsule formulations, so as to enhance the
performance characteristics of the capsule formulation during processing
and/or the performance characteristics and/or physical properties of the
finished capsule product.

[0022] The polymer modifier of the present invention is included in the
soft capsule of the present invention in order to alter one or more
physical and/or chemical characteristics of the gel-forming polymers that
are contained in the capsule formulations. As an example, the polymer
modifier may reduce the melting point of the gel-forming polymer in the
matrix formulation. With the melting point reduced, less heat is required
to place the gel-forming polymer in a liquid state, thereby reducing the
energy cost and time required to process the formulation and allowing the
incorporation of heat-sensitive drugs or agents.

[0023] In addition to a possible reduction in the melting point of the
gel-forming polymer, the polymer modifier may reduce the viscosity of one
or more of the gel-forming compositions found in the capsule formulation,
thereby providing a formulation that may flow more easily during
processing (a "flowable" composition). Again, capsule manufacturing may
be facilitated by such an alteration. Gel modifier can also prevent gel
hardening upon gel storage and improve the disintegration and dissolution
of the chewable products in the mouth.

[0024] A third illustrative example of the effect that the polymer
modifier may have is a reduction of the molecular weight of one or more
gel-forming polymers of the capsule formulation. Such a reduction also
tends to affect other physical properties of the gel-forming polymers,
both during capsule production and in the finished capsule product. The
polymer modifier of the present invention also may enhance the texture or
chewiness of the finished soft capsule. The capsule texture may tend to
be less "leathery" than it would be in the absence of the polymer
modifier, thereby providing a more acceptable mouth feel for the capsule
user.

[0025] Although these particular examples are set forth herein describing
the possible impact the polymer modifier has upon the capsule formulation
and the finished capsule product, these examples are provided for the
purpose of illustration and not to limit the scope of the present
invention. These specific possible effects need not occur in order for a
capsule formulation to fall within the scope of the present invention.
Indeed, these and/or other effects may be realized by the inclusion of a
polymer modifier into a capsule formulation, thereby providing a soft
capsule that is acceptable for chewing.

[0026] Soft gel capsules generally are produced by a rotary die process as
set forth by J. P. Stanley in "The Theory and Practice of Industrial
Pharmacy," L. Lachman, (editor), Lea and Febiger (publisher),
Philadelphia (1976), which is incorporated by reference as if fully set
forth herein. In the process of the invention, a molten mass of a
gel-forming polymer, such as, for example, a gelatin formulation, is fed
from a reservoir onto drums to form two spaced sheets or ribbons of
gelatin in a semi-molten state. These ribbons are fed around rollers and
brought together at a convergent angle into the nip of a pair of roller
dies that include opposed die cavities. A matrix containing an active
ingredient to be encapsulated is fed into the wedge-shaped joinder of the
ribbons.

[0027] The gelatin ribbons are continuously conveyed between the dies,
with portions of the matrix being trapped between the sheets inside the
die cavities. The sheets are then pressed together, and severed around
each die so that opposed edges of the sheets flow together to form a
continuous gelatin sheath around the entrapped medicament. The part of
the gelatin sheet that is severed from the segments forming the capsules
may then be collected for recycling. The very soft capsules are then
dried to increase the integrity of the sheath, and packaged for later
distribution and consumption.

[0028] The chewable soft capsules of the present invention are generally
formed by combining the gel-forming composition, polymer modifier,
plasticizer, and water with or without mixing, and while maintaining the
heat of the mixture in a range between about 40 and about 75 degrees
Celsius. This matrix mixture is then allowed to incubate for about 4 to
about 72 hours, while its temperature is maintained in the range of about
40 to about 75 degrees Celsius. The matrix mixture is then cooled to a
temperature in the range of about 30 to about 40 degrees Celsius.

[0029] The matrix mixture is then encapsulated. The capsules are then
air-cooled to a temperature in the range of about 5 to about 25 degrees
Celsius. The capsules are also dried to a final water content of a range
of about 5 to about 20 percent by weight. Final water content can also be
from about 5 to about 10 percent. Prior to drying, the matrix can
comprise water from about 20% to about 50% by weight. Prior to drying,
water content can also be about 25% to about 35% by weight. Active
ingredients can be added from the start of preparing the gel mass, if
they are chemically and physically stable. Unstable actives can be added,
preferably as a last step before encapsulation to minimize any
possibility for degradation. The performance properties of a gel-forming
composition are affected in part by its cohesive strength, which, in the
case of at least gelatin, is expressed as "bloom." This bloom value is
determined by measuring the weight in grams required to move a plunger
0.5 inch in diameter, 4 mm into a 6.67% gelatin gel that has been held
for 17 hours at 10° C.

[0030] Chewable soft gel capsules are designed to at least partially
disperse or dissolve in the user's mouth, upon chewing, within a brief
period of time so that the chewable mass can be swallowed. Therefore, in
addition to the above properties, the remains of the capsule should tend
to be soluble after the active ingredient has been released. These
remains should also have a good "mouth feel." As used herein, "mouth
feel" describes chewability. Chewing the capsule remains should be a
pleasant, or at least not an unpleasant, sensation that results in a
swallowable composition.

[0031] Surprisingly, it has been found that a chewable soft capsule having
these desired characteristics can be produced from a capsule formulation
including an appropriate amount of polymer modifier that alters one or
more characteristics of the gel-forming composition therein. Such a
capsule formulation, examples of which are provided below, has. been
found to produce chewable soft capsules that exhibit a desirable
mouth-feel and solubility.

[0032] In one embodiment, the matrix formulation, prior to drying, of the
present invention includes the following ingredients in the specified
percentages:

[0033] The gel-forming polymer of the above embodiment may be a gelatin
that exhibits a bloom in the range of about 0 to about 250. The
plasticizer may be a polyol, such, for example, glycerol, sorbitol,
maltitol, xylitol, or combinations thereof. The polymer modifier may be a
mono, di, or poly carboxylic acid. More specifically, the polymer
modifier may be lactic acid, fumaric acid, tartaric acid, citric acid,
glycolic acid or a combination of two or more of these acids.

[0034] In this embodiment, the capsule may also include a sheath
formulation (before drying) including the following ingredients in the
specific ranges:

[0035] As with the matrix formulation, the gel-forming polymer may be a
gelatin. The gelatin may exhibit a bloom in the range of about 80 to
about 250. The plasticizer of this sheath formulation may be a polyol,
such as, for example, a polyol selected from glycerol, sorbitol,
maltitol, xylitol, or combinations thereof.

[0036] In another embodiment, the matrix formulation includes the
following ingredients in the specified ranges, after drying:

[0037] Again, the matrix formulation may include a gelatin as the
gel-forming polymer. In this instance, the gelatin may exhibit a bloom in
the range of about 0 to about 80. Likewise, the plasticizer may be a
polyol, such as one selected from the list set forth above. Also, the
polymer modifier again may be a carboxylic acid, such as one selected
from the list above.

[0038] In this embodiment, the capsule formulation also may include a
sheath that includes the following ingredients in the specified ranges:

[0039] The gel-forming polymer of this sheath formulation may be a
gelatin, which exhibits a bloom in the range of about 100 to about 175.

[0040] It will be understood that different percentages may be selected
within the above ranges so that the sum of the percentages of the sheath
ingredients is equal to 100%. If additional ingredients are used, the
percentages will be adjusted within the ranges listed to accommodate the
additional ingredients.

[0041] In the case of a capsule formulation including both a matrix and a
sheath, the matrix may include a first gel-forming polymer and a first
plasticizer and the sheath may include a second gel-forming polymer and a
second plasticizer. Depending upon the specific formulation, the first
and second gel-forming polymers may be either identical to each other or
differ in their chemical compositions, bloom values and/or amounts.
Likewise, the first and second plasticizers may be identical or differ in
their compositions and/or amounts.

[0042] The chewable soft capsule formed from the above mixture, after
being dried for storage and subsequent use, is comprised of the following
ingredients in the specified parts by weight:

[0043] The following examples describe the manufacture and testing of
various matrix formulations for acceptable practice.

[0044] Gelatin, gelatin hydrolysate, and glycerol were mixed and heated to
about 65° C. overnight. Citric acid was then added and masses were
molded and dried at 20° C. under low humidity (20-30%) until the
total water content reached about 10%. Dried samples were tested for
hardness, water content, and other texture analysis. The hardness ranged
from about 1 to about 100 gram force, using a texture analyzer fitted
with a round ball probe. The following example formulations are provided
for purposes of illustration of certain aspects of the present invention
and are not intended to limit the scope thereof. The optimum percentages
of each ingredient will depend upon the overall formulation contents, and
the identity of the individual ingredients. However, evaluation and
selection of the most desirable formulation will be well within the skill
of practitioners in this area, once they are familiar with the present
disclosure. The values provided in Table 1 for each compound represent
the parts per weight of that compound, and the corresponding hardness
obtained:

Hardness was measured after drying. The above amounts are in weight
ratios. Water was adjusted so that the water % is constant and around 28%
of the mass before drying. A complete gel hydrolysate is a hydrolyzed
gelatin that has zero bloom (as used herein, the term "hydrolysate" may
indicate a partial or complete hydrolysate, as indicated in the context
where the term is used).

Example 6

A Soft Chewable Capsule Composition

[0045] A soft chewable capsule composition according to the invention can
include the following matrix and sheath:

[0046] A gel matrix consisting 14.6% gelatin (60-80 bloom), 14.6%
glycerin, 14.6% Sorbitol Special® (SPI Polyols, Inc., New Castle,
Del.), 40% water (before drying) and 1.48% citric acid was made by
subjecting the mixture to heat at 60° C. for about 2 hours. The
cooked matrix had a melting point of 29° C. After 24 hours of
incubation, the same matrix had a melting point of 25.3° C. and
its viscosity was reduced to 52% of the initial value, as measured by a
cone and plate rheometer (TA instruments, Leatherhead, England).

[0048] Gelatin and gel hydrolysate were dissolved in water in presence of
the plasticizer at about 60° C. The polymer modifier was also
added to the mass and was allowed to modify the mass structure by
incubation at 60° C. for 12 hours. The above matrix formula had
water activity of 0.39. After incubation, encapsulation was performed
using a rotary die machine, with the following gel sheath composition:

[0049] Capsules were dried in a tumble drier where cold air was initially
used to congeal the capsule mass and keep the shell shape integrated.
Drying was then completed using a tunnel dryer. Dried capsules had a 9.8%
water content, and firm texture (a hardness peak of 91.9 gram force) as
measured using a TA-XT2 texture analyzer (Texture Technologies,
Scarsdale, New York) using a standard two bite texture profile analysis
with a 0.25 inch diameter probe at room temperature.

[0051] Gelatin and gel hydrolysate were dissolved in water in presence of
the plasticizer at about 60° C. The polymer modifier was also
added to the mass and was allowed to modify the mass structure by
incubation at 60° C. for 12 hours. After incubation, encapsulation
was performed using a rotary die machine, with the following gel sheath
composition:

[0052] Capsules were dried in a tumble drier where cold air was initially
used to congeal the capsule mass and keep the shell shape integrated.
Drying was then completed using a tunnel dryer. Dried capsules had a 10%
water content, and softer texture (a hardness peak of 22.7 gram force) as
measured using a TA-XT2 texture analyzer using a standard two bite
texture profile analysis with a 0.25 inch diameter probe at room
temperature.

Example 10

Chewable Soft Capsule Matrix Containing Active Ingredient in Solution

[0053] A chewable soft capsule formulation contains 6.25 mg per unit dose
of the antihistaminic, diphenhydramine, was manufactured using the
methods explained in examples 9 and 10 where the active was incorporated
to the fill matrix after the incubation with the polymer modifier.

[0055] A chewable soft capsule matrix containing 80 mg per dose of the
analgesic antipyretic active, Paracetamol was manufactured using the
methods explained in examples 9 and 10 where the active was incorporated
to the fill matrix after the incubation with the polymer modifier.

[0057] Certain modifications and improvements will occur to those skilled
in the art upon a reading of the foregoing description. It should be
understood that all such modifications and improvements are properly
within the scope of the following claims.

Patent applications by Emadeldin M. Hassan, Greensboro, NC US

Patent applications in class Liquid encapsulation utilizing an emulsion or dispersion to form a solid-walled microcapsule (includes liposome)

Patent applications in all subclasses Liquid encapsulation utilizing an emulsion or dispersion to form a solid-walled microcapsule (includes liposome)